The functional relationship between the ets gene of transforming leukemia virus, E26, and its cellular prototypes has been facilitated by structural comparisons at the nucleic acid and predicted protein levels. We have determined the complete nucleotide sequence of the chicken, mouse and human ets-1 and ets-2 genes and compared them to each other and to the ets gene of 12-6. The human ETS-1 gene product is over 95% identical to the chicken and mouse ets-1 genes. The mammalian ets-2 genes from man and mouse encode for nearly identical amino acids and are over 90% conserved relative to the chicken ets-I gene. Alignment of the predicted ets proteins suggests that three domains exist. The domain closest to the carboxyl-termini is highly conserved in the predicted gene products from species ranging from human to Drosophila. The domain located at the amino-terminal end of the ets proteins is more divergent, being highly conserved only between the same gene isolated from different species (e.g., chicken ets-I vs. human ETS-1; mouse ets-2 vs. human ETS-2). The central domain encoding the ets proteins is found to be most divergent, even between ets family genes of the same species. Thus, ets represents a family of genes whose members are diverging at variable rates. We have characterized the genomic structure of the human ETS1 and ETS2 genes and find that while the ETS1 locus consists of eight exons over 65 b, the ETS2 gene contains 10 exons spanning 25 kb. The genes have similar exon/intron organization for those exons that encode similar amino acids, suggesting that the genes evolved from each other. The ETS1 and ETS2 genes have transcript complexity due to multiple initiation sites, alternate splicing and multiple polyadenylation sites. They represent members of an increasingly large family of genes lacking TATA/CAAT promoter elements. With the clones now available, the molecular basis for the differential regulation of the ets-I and ets-2 genes may be understood. The ets-2 gene appears to have mitogenic activity in transfected cells.